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Corticosterone Regulation of 5-HT2A Receptor-Mediated Behaviors: Attenuation by Melatonin

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Corticosterone Regulation of 5-HT2A Receptor-Mediated Behaviors: Attenuation by Melatonin Physiology & Behavior, Vol. 67, No. 3, pp. 439–442, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0031-9384/99/$–see front matter PII S0031-9384(99)00096-7 Corticosterone Regulation of 5-HT2A Receptor-Mediated Behaviors: Attenuation by Melatonin BORIS B. GORZALKA,1 LORI A. BROTTO AND JANIE J. HONG Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4 Received 15 February 1999; Accepted 26 April 1999 GORZALKA, B. B., L. A. BROTTO AND J. J. HONG. Corticosterone regulation of 5-HT2A receptor-mediated behav- iors: Attenuation by melatonin. PHYSIOL BEHAV 67(3) 439–442, 1999.—The effects of chronic corticosterone treatment on sexual behavior and on wet-dog shakes (WDS), a serotonergic type 2A (5-HT2A) receptor-mediated behavior, were explored in the male rat. In addition, the effects of acute melatonin treatment, both alone and in combination with corticosterone, were investigated. Chronic injections of corticosterone resulted in an overall decrease in consummatory measures of sexual behav- ior, and an increase in WDS. Furthermore, although an acute injection of melatonin alone had no effect on any recorded be- havior, it attenuated the effects of corticosterone on sexual behavior and WDS. The data suggest that in the context of 5-HT2A receptor-mediated behaviors, melatonin has possible implications as a 5-HT2A antagonist. © 1999 Elsevier Science Inc. Melatonin Corticosterone Serotonin 5-HT2A receptor Sexual behavior IN the male rat, serotonergic type 2A (5-HT2A) receptor ac- some regulatory effects on the 5-HT2A receptor. Chronic cor- tivity has been reliably found to modulate an inhibition of sex- ticosterone treatment has been demonstrated to significantly ual behavior (15). Furthermore, the frequently employed be- increase the density of central 5-HT2A receptors (9,21,26), and havior known as “wet-dog shakes” (WDS) has been found to to significantly facilitate 5-HT2A receptor-mediated behaviors be largely mediated by 5-HT2A activity, with activation of the (3,13,18). 5-HT2A receptor producing a robust facilitation of WDS in the The hormone, melatonin, has also been explored in the rat (29). WDS, which consist of a rotational shudder of the up- context of 5-HT2A receptor regulation. Eison et al. (8) demon- per body (2), resemble the purposeful movement, as seen in strated a dose-dependent attenuation by melatonin of the in- dogs, and have reliably been used as a behavioral assay of crease in WDS induced by a 5-HT2A receptor agonist. More- 5-HT2A receptor activity (29). A strong, inverse correlation over, radioligand binding techniques demonstrated that melatonin exists between male sexual behavior and WDS, such that acti- reduced the concentration-dependent 5-HT2A-mediated phos- vation of the 5-HT2A receptor produces an increase in WDS, phoinositide (PI) hydrolysis response to 5-HT2A agonists and a concomitant decrease in sexual behavior (27). As a re- without altering central 5-HT2A receptor density (8). Further- sult, spontaneously occurring WDS have been frequently em- more, investigations that demonstrate a similarity in the be- ployed as a noninvasive index of 5-HT2A activity during sexual havioral effects of melatonin to 5-HT2A antagonists (10) are behavior. consistent with melatonin’s putative 5-HT2A antagonism. Unique to the 5-HT2A receptor is its “nonclassical” mecha- Given the apparently opposing effects of corticosterone nism of regulation (24). The receptor’s relative resistance to and melatonin on 5-HT2A receptor activity, it seems reason- upregulation in response to serotonergic manipulation has able to predict that concurrent administration of melatonin triggered an interest in nonserotonergic methods of its regula- would attenuate the behavioral effects of corticosterone treat- tion. For example, the adrenal hormone, corticosterone, has ment. Furthermore, because drugs that antagonize 5-HT2A re- been explored in this context, and has been found to exert ceptor activity, including ritanserin, pirenperone, ketanserin, 1To whom requests for reprints should be addressed. E-mail: [email protected] 439 440 GORZALKA, BROTTO AND HONG and nefazodone, exert no effects on sexual behavior (28) and val. In addition, the frequency of WDS was tallied for a 30- WDS (18), it is expected that neither should melatonin, a pu- min observation period. tative 5-HT2A antagonist, exert effects on these measures All testing was conducted during the middle third of the when administered alone. The aim of the present study is to dark cycle by trained observers blind to the experimental con- investigate the effects of corticosterone, both alone and in ditions of the animals. A priori predictions that 1) melatonin combination with melatonin, on sexual behavior and WDS, should attenuate the effects of corticosterone, 2) melatonin and to explore the possibility of 5-HT2A antagonism as a result alone should not exert any behavioral effects, and 3) cortico- of melatonin treatment. sterone alone should produce behavioral effects that differ from the other three conditions, and that are similar to each other, permit use of the statistical method of nondirectional Planned MATERIALS AND METHODS Contrasts (11), with a significance level preset at p , 0.05. Subjects RESULTS Eighty Long–Evans male rats (Charles River Canada Inc., Quebec), were obtained at 5 weeks of age. Prior to testing, Table 1 suggests that corticosterone inhibited sexual be- males were screened for copulatory proficiency, and those havior and increased WDS, and that these effects were atten- displaying consistently vigorous sexual activity were selected uated by melatonin. Planned comparisons revealed that corti- for the study. The screening procedure resulted in 68 males costerone significantly decreased the frequency of ejaculations being employed in the study. At the time of testing, males compared to the control, melatonin-treated, and corticoste- were 4.5 months of age and 475 g on average. In addition, 18 rone combined with melatonin-treated groups, as a whole, sexually experienced female rats were used to elicit sexual be- t(64) 5 2.03, p 5 0.047. Also, melatonin significantly attenu- havior in the males. Females were previously bilaterally ova- ated the effects of corticosterone on ejaculations, t(64) 5 2.17, riectomized at 3 months of age using standard surgical proce- p 5 0.034. Melatonin alone did not affect ejaculation fre- dures while anesthetized with ketamine HCl (75 mg/kg) and quency, p . 0.05. xylazine (7 mg/kg) obtained from the UBC Animal Care Cen- A similar pattern was observed for ejaculation latency. tre, Vancouver, Canada. Melatonin significantly blocked the effects of corticosterone, All rats were housed in same-sex groups of three or four, t(64) 5 22.24, p 5 0.028. Although not statistically signifi- in standard wire mesh cages, and were allowed free access to cant, corticosterone increased the ejaculation latency com- Purina Rat Chow and water. Colony conditions were main- pared to the other three conditions as a group, t(64) 5 tained at 21 6 18C, and animals were kept on a reverse 12/12- 21.848, p 5 0.069. Again, melatonin alone had no effect on h light cycle (lights off at 0900 h). ejaculation latency, p . 0.05. For mounting behavior, corticosterone significantly in- Injection Procedure creased the frequency of mounts compared to the other three conditions as a group, t(33) 5 22.503, p 5 0.017. Whereas Corticosterone-21-acetate (Sigma Chemical Co., Chicago, melatonin appeared to block the effects of corticosterone on IL) was suspended in propylene glycol (20 mg/mL) and mela- mounts, this effect did not quite reach statistical significance, tonin (Sigma Chemical Co) was dissolved in a solution of 20% p . 0.05. Although similar trends were observed on some dimethyl sulfoxide (DMSO) and saline (6 mg/mL). Cortico- other measures of sexual behavior, there was no significant ef- sterone or the vehicle, propylene glycol, was injected subcuta- fect of either corticosterone or melatonin treatment on mount neously for 14 days (1 mL/kg). On the 15th day, animals re- latency, intromission latency, intromission frequency, and post- ceived an intraperitoneal injection of either melatonin (1 mL/ ejaculatory interval. kg), or the vehicle, DMSO, 45 min prior to testing. In addi- Corticosterone significantly increased WDS relative to the tion, given previous evidence that the frequency of spontane- other three conditions as a group, t(64) 5 23.969, p 5 0.001. ously occurring WDS is quite low in males engaging in copula- In addition, melatonin significantly attenuated the effects of tory behavior (4), all animals received as injection (1 mL/kg) corticosterone on WDS, t(64) 5 23.803, p 5 0.001. Again, of the 5-HT receptor agonist, (1)1-(2,5 dimethyl-4-iodo- 2A melatonin alone had no effect on WDS, p . 0.05. phenyl)-2-aminopropane (DOI; Research Biochemicals In- ternational), to amplify this effect. DOI was dissolved in 0.9% saline (1.25 mg/mL), 30 min prior to testing. Male subjects were randomly assigned to one of four treatment groups: 1) DISCUSSION propylene glycol and DMSO, n 5 18; 2) propylene glycol and The present results support previous findings of a cortico- melatonin, n 5 20; 3) corticosterone and DMSO, n 5 15; and sterone-induced inhibition of sexual behavior in the male rat 4) corticosterone and melatonin, n 5 15. (13) and facilitation of WDS (3,18). The chronic corticoste- rone regimen employed in these studies results in plasma cor- Behavioral Testing Procedure ticosterone levels that are similar to those produced after a Females were injected subcutaneously with 10 mg estradiol chronic stressor (22), and various stressors have been found to benzoate (Sigma Chemical Co.) 2 days before testing, and 500 inhibit sexual behavior and facilitate WDS in the male rat mg progesterone (Sigma Chemical Co.), 4 h before testing.
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